I've disconnected my HDD after force shut down, from the system menu and during bootmii, but never during a game, or while a loader is on.

The safest way I would assume would be after the Wii has shut off. That is, when the Wii's light is red. But I guess it should be okay to disconnect it as long as there is no reading or writing to or from the HDD, which occurs when you have a Loader running, or a game running, or if you have any apps that connect to the USB.